crossing96/oncoscreening huggingface dataset:
The KLF16/MYC feedback loop is a therapeutic target in bladder cancer.	BACKGROUND: Bladder cancer (BLCA) is a common malignancy characterized by dysregulated transcription and a lack of effective therapeutic targets. In this study, we aimed to identify and evaluate novel targets with clinical potential essential for tumor growth in BLCA. METHODS: CRISPR-Cas9 screening was used to identify transcription factors essential for bladder cancer cell viability. The biological functions of KLF16 in bladder cancer were investigated both in vitro and in vivo. The regulatory mechanism between KLF16 and MYC was elucidated through a series of analyses, including RNA sequencing, quantitative polymerase chain reaction (qPCR), RNA immunoprecipitation, Western blotting, Mass spectrometry, Dual-luciferase reporter assays, Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing, OptoDroplets assays, and RNA stability assay. The clinical relevance of KLF16 and MYC in bladder cancer was evaluated through analyses of public databases and immunohistochemistry. RESULTS: Krüppel-like factor 16 (KLF16) was essential for BLCA cell viability. Elevated expression of KLF16 was observed in bladder cancer tissues, and higher expression levels of KLF16 were correlated with poor progression-free survival (PFS) and cancer-specific survival (CSS) probabilities in BLCA patients. Mechanistically, KLF16 mRNA competed with the mRNA of dual-specificity phosphatase 16 (DUSP16) for binding to the RNA-binding protein, WW domain binding protein 11 (WBP11), resulting in destabilization of the DUSP16 mRNA. This, in turn, led to activation of ERK1/2, which stabilized the MYC protein. Furthermore, KLF16 interacted with MYC to form nuclear condensates, thereby enhancing MYC's transcriptional activity. Additionally, MYC transcriptionally upregulated KLF16, creating a positive feedback loop between KLF16 and MYC that amplified their oncogenic functions. Targeting this loop with bromodomain inhibitors, such as OTX015 and ABBV-744, suppressed the transcription of both KLF16 and MYC, resulting in reduced BLCA cell viability and tumor growth, as well as increased sensitivity to chemotherapy. CONCLUSIONS: Our study revealed the crucial role of the KLF16/MYC regulatory axis in modulating tumor growth and chemotherapy sensitivity in BLCA, suggesting that combining bromodomain inhibitors, such as OTX015 or ABBV-744, with DDP or gemcitabine could be a promising therapeutic intervention for BLCA patients.	bladder
Pitfalls of frozen section diagnosis in ureter margin evaluation of plasmacytoid urothelial carcinoma of urinary bladder.	BACKGROUND: Plasmacytoid urothelial carcinoma (PUC) is a rare and aggressive subtype that often presents at advanced stages with poor prognosis. This study investigated tumor invasion to better understand tumor behavior and potentially to improve management strategies by comparing the clinicopathologic characteristics of PUC with positive ureter resection margin (+ URM) with PUC with negative URMs (-URM). METHODS: This retrospective analysis used pathology reports from 2017 to 2023 for cases diagnosed with PUC during radical cystectomy (RC). All applicable H&E slides of RC specimens were reviewed. Cases with a plasmacytoid component greater than 25% in the RC specimens were analyzed. Frozen section analyses (FSAs) and permanent section analyses (PSAs) of ureter resection margins were performed. RESULTS: Fifteen patients with a plasmacytoid component greater than 25% in their RC specimens were identified. Compared with -URM PUC cases, +URM PUC cases were located more frequently at the trigone or bladder neck, and all + URM cases exhibited ureter orifice involvement. Among 6 PSA-positive cases, three (50%) cases showed discrepancies with FSA. Three + URM cases exhibited PUC tumor cells along the submucosa and muscularis propria layer, and the 3 remaining cases showed PUC tumor cells along the adventitia. We observed a consistent adventitia invasion in all the discordant cases, with sectioning errors and misinterpretation identified as the primary causal factors. CONCLUSION: To the best of our knowledge, this is the first study to demonstrate two separate patterns of tumor infiltration along the ureter and to discuss the significance of comparing FSA with PSA in PUC. The significance of comprehensive management strategies for PUC patients, including a thorough evaluation of ureteral margins and accurate interpretation of periureteral fat tissue, is highlighted. Large, well-designed studies are needed to strengthen the evidence and to establish optimal management strategies for patients with PUC.	bladder
Urease-powered nanomotor containing STING agonist for bladder cancer immunotherapy.	Most non-muscle invasive bladder cancers have been treated by transurethral resection and following intravesical injection of immunotherapeutic agents. However, the delivery efficiency of therapeutic agents into bladder wall is low due to frequent urination, which leads to the failure of treatment with side effects. Here, we report a urease-powered nanomotor containing the agonist of stimulator of interferon genes (STING) for the efficient activation of immune cells in the bladder wall. After characterization, we perform in vitro motion analysis and assess in vivo swarming behaviors of nanomotors. The intravesical instillation results in the effective penetration and retention of nanomotors in the bladder. In addition, we confirm the anti-tumor effect of nanomotor containing the STING agonist (94.2% of inhibition), with recruitment of CD8(+) T cells (11.2-fold compared with PBS) and enhanced anti-tumor immune responses in bladder cancer model in female mice. Furthermore, we demonstrate the better anti-tumor effect of nanomotor containing the STING agonist than those of the gold standard Bacille Calmette-Guerin therapy and the anti-PD-1 inhibitor pembrolizumab in bladder cancer model. Taken together, the urease-powered nanomotor would provide a paradigm as a next-generation platform for bladder cancer immunotherapy.	bladder
PD-1 blockade plus cisplatin-based chemotherapy in patients with small cell/neuroendocrine bladder and prostate cancers.	Small cell neuroendocrine cancers share biologic similarities across tissue types, including transient response to platinum-based chemotherapy with rapid progression of disease. We report a phase 1b study of pembrolizumab in combination with platinum-based chemotherapy in 15 patients with stage III-IV small cell bladder (cohort 1) or small cell/neuroendocrine prostate cancers (cohort 2). Overall response rate (ORR) is 43% with two-year overall survival (OS) rate of 86% (95% confidence interval [CI]: 0.63, 1.00) for cohort 1 and 57% (95% CI: 0.30, 1.00) for cohort 2. Treatment is tolerated well with grade 3 or higher adverse events occurring in 40% of patients with no deaths or treatment cessation secondary to toxicity. Single-cell and T cell receptor sequencing of serial peripheral blood samples reveals clonal expansion of diverse T cell repertoire correlating with progression-free survival. Our results demonstrate promising efficacy and safety of this treatment combination and support future investigation of this biomarker. This study was registered at ClinicalTrials.gov (NCT03582475).	bladder
Psychological Distress in Bladder Cancer Patients: A Systematic Review.	OBJECTIVE: Bladder cancer patients experience high levels of disease and treatment-related distress, however, factors that can mitigate patient-reported psychological distress are poorly characterized. Thus, this study serves to summarize the burden of psychological distress among bladder cancer patients and identify clinical, psychological, and socioeconomic factors that are associated with varying levels of psychological distress. METHODS: We performed a systematic review of studies examining psychological distress in bladder cancer patients. We searched PubMed/MEDLINE, Embase, and PsycINFO from October 2000 to February 2024 according to the PRISMA guidelines. Associations between clinical, psychological, socioeconomic factors, and psychological distress were identified in each study and extracted. The protocol for this review is registered in PROSPERO (CRD42024495568). RESULTS: Using our search strategy, 759 articles were retrieved and 17 met inclusion criteria, representing 2572 bladder cancer patients. Tumor stage (n = 3), younger age (n = 2), female sex (n = 2) the preoperative setting (n = 2), depression/anxiety (n = 2), and negative psychological response to illness (n = 2) were common factors associated with increased psychological distress. Transitioning from the preoperative to the postoperative period (n = 2), postoperative inpatient rehabilitation (n = 2), feeling well informed (n = 2), and social support (n = 2) were associated with decreased psychological distress. CONCLUSION: While clinical factors associated with increased psychological distress are nonmodifiable, clinical, psychological, and socioeconomic factors associated with decreased psychological distress can be improved upon by healthcare providers to mitigate the distress that bladder cancer patients experience.	bladder
[Urinary bladder: tumor precursors and non-invasive carcinoma].	BACKGROUND: In recent years, our understanding of the genesis and development of urothelial carcinomas (UC) has expanded considerably thanks to advancing molecular classifications. These advances have led to significant changes in the 5th edition of the WHO classification of tumors of the urinary tract and male genitalia. The new findings allow both the introduction of modern diagnostic approaches and a return to proven methods in the evaluation of precursor lesions and non-invasive carcinomas. AIMS: This article is intended to provide a summarized overview of the various precursor lesions and pathways of urothelial carcinoma. RESULTS AND DISCUSSION: The changes and clarifications in the 5th edition of the WHO classification reflect the progress made in the molecular and morphological characterization of urothelial carcinomas. These adjustments provide an improved basis for diagnosis and treatment and emphasize the importance of differentiated molecular profiles for the classification and treatment of UC. Despite all this, conventional histology remains the gold standard for the diagnosis and classification of non-invasive carcinomas and precursor lesions.	bladder
Myeloid-Derived Suppressor Cells in Bladder Cancer: An Emerging Target.	Bladder cancer remains a prevalent and challenging malignancy. Myeloid-derived suppressor cells (MDSCs) have emerged as key contributors to the immunosuppressive tumor microenvironment, facilitating tumor progression, immune evasion, and resistance to therapies. This review explores the role of MDSC in bladder cancer, highlighting their involvement in immune regulation; tumor progression; and resistance to therapies such as bacillus Calmette-Guérin (BCG) therapy, chemotherapy, and immune checkpoint inhibitors (ICIs). We also discuss their potential as biomarkers and therapeutic targets, with current evidence suggesting that targeting MDSCs, either alone or in combination with existing treatments such as BCG and ICIs, may enhance anti-tumor immunity and improve clinical outcomes. However,, challenges remain, particularly regarding the identification and therapeutic modulation of MDSC subpopulations. Further research is warranted to fully elucidate their role in bladder cancer and to optimize MDSC-targeted therapies.	bladder
Targeting ketone body metabolism in mitigating gemcitabine resistance.	Chemotherapy is often combined with surgery for muscle invasive and nonmuscle invasive bladder cancer (BCa). However, 70% of the patients recur within 5 years. Metabolic reprogramming is an emerging hallmark in cancer chemoresistance. Here, we report a gemcitabine resistance mechanism that promotes cancer reprogramming via the metabolic enzyme OXCT1. This mitochondrial enzyme, responsible for the rate-limiting step in β-hydroxybutyrate (βHB) catabolism, was elevated in muscle invasive disease and in patients with chemoresistant BCa. Resistant orthotopic tumors presented an OXCT1-dependent rise in mitochondrial oxygen consumption rate, ATP, and nucleotide biosynthesis. In resistant BCa, knocking out OXCT1 restored gemcitabine sensitivity, and administering the nonmetabolizable βHB enantiomer (S-βHB) only partially restored gemcitabine sensitivity. Suggesting an extrametabolic role for OXCT1, multi-omics analysis of gemcitabine sensitive and resistant cells revealed an OXCT1-dependent signature with the transcriptional repressor OVOL1 as a master regulator of epithelial differentiation. The elevation of OVOL1 target genes was associated with its cytoplasmic translocation and poor prognosis in a cohort of patients with BCa who have been treated with chemotherapy. The KO of OXCT1 restored OVOL1 transcriptional repressive activity by its nuclear translocation. Orthotopic mouse models of BCa supported OXCT1 as a mediator of gemcitabine sensitivity through ketone metabolism and regulating cancer stem cell differentiation.	bladder
Effect of intraoperative methadone in robot-assisted cystectomy on postoperative opioid requirements: A randomized clinical trial.	BACKGROUND: Postoperative pain management is a challenge after robot-assisted cystectomy (RAC). Methadone has a long duration of action, and we therefore hypothesized that a single dose of intraoperative methadone would reduce postoperative opioid requirements and pain intensity in bladder cancer patients undergoing RAC. METHODS: We conducted a blinded randomized controlled clinical trial from July 2020 to August 2023. Patients scheduled to undergo RAC because of bladder cancer were randomized to receive intraoperative methadone (0.15 mg/kg(-1)) or morphine (0.15 mg kg(-1)) 1 h before endotracheal extubation. The primary outcome was opioid requirements after 24 h. Secondary outcomes were opioid requirements after 3 h, pain intensity at rest and during coughing, postoperative nausea and vomiting (PONV), sedation, hypoxemia, hypoventilation, time spent in the post-anesthetic care unit, and patient satisfaction. RESULTS: A total of 114 patients were randomized. Data from 99 patients (14 females, 85 males; mean age 69.8 ± 8.9 years) were available for analysis; 52 received methadone and 47 received morphine. Opioid consumption was similar between the methadone group and morphine group at 3 h (median, mg, 45 (IQR 30 to 75) vs. 45 (IQR 15 to 82.5) p = .97) and at 24 h (median, mg, 125 (IQR 75 to 198.5) versus 105 (IQR 72 to 157.5), p = .29). Pain intensity was significantly lower in the morphine group at 48 h compared with the methadone group. Patient satisfaction at 24 h was increased in the methadone group compared with the morphine group (median, (IQR), NRS; 9 (IQR 7 to 10) versus 7 (IQR 4 to 9), p = .020). There were no differences between treatment groups in terms of time spent in the post-anesthetic care unit and the occurrence of opioid-related side effects. CONCLUSION: A single dose of intraoperative methadone does not reduce postoperative opioid requirements compared with a single dose of morphine in bladder cancer patients undergoing RAC.	bladder
[Clinicopathological Features and Outcomes of Perioperative Treatment for Small Cell Carcinoma of the Bladder].	OBJECTIVE: Small cell carcinoma of the bladder (SCCB) is a rare malignant tumor of the bladder. This study aims to explore its clinicopathological features and prognostic factors and to explore the role of perioperative treatment methods. METHODS: The clinical data of SCCB patients admitted to West China Hospital, Sichuan University over 8 years from January 2016 to January 2024 were collected. The clinicopathological features of SCCB were summarized. The survival outcomes and prognostic factors were analyzed. The effect of perioperative treatment on the improvement in prognosis was explored. RESULTS: A total of 31 confirmed cases of SCCB were enrolled. We observed a number of clinicopathologic features. All cases had advanced clinical staging, with the T staging status being above T2 in all cases, and distant metastasis was found in 23% of the newly diagnosed cases. A high proportion of the SCCB cases were combined with other histologic types, with 96% showing combination with urothelial carcinoma (UC). The SCCB patients had a poor prognosis, presenting a median survival of 12 months, 1-year overall survival (OS) of 57.9%, and 3-year OS of 27.6%. Patients with extensive-stage SCCB had a significantly worse prognosis than those with limited-stage SCCB did (median OS time of 17.0 months vs. 4.4 months, P<0.05). In limited-stage SCCB, the median OS of patients who underwent radical cystectomy (RC) was 19.9 months, while that of the patients who did not undergo RC was 15.2 months (P<0.05). The OS of patients who received perioperative therapy in combination with RC had longer OS than those who received only RC did (P<0.05). Among these, patients recevied neoadjuvant therapy (NAT) had a significantly longer OS than patients who didn't receive NAT (P<0.05). Subgroup analysis revealed that patients who were responsive to neoadjuvant therapy had longer disease-free survival and longer OS than those who were not responsive did (P<0.05). Lymph node metastasis was an independent factor of poor prognosis (hazard ratio [HR]=15.21, 95% confidence interval [CI]: 1.732-133.912, P=0.014). NAT prior to RS was an independent protective factor, significantly reducing the risk of death compared with RC alone (HR=0.03, 95% CI: 0.001-0.724, P=0.031). CONCLUSION: RC is an effective treatment that prolongs the survival of patients with limited-stage SCCB. RS combined with NAT can further improve their survival.	bladder
Prognostic value of neutrophil-to-lymphocyte ratio in patients with non-muscle-invasive bladder cancer with intravesical Bacillus Calmette-Guérin immunotherapy: a systematic review and meta-analysis.	BACKGROUND: The predictive accuracy of the preoperative neutrophil-to-lymphocyte ratio (NLR) on the prognosis of patients with non-muscle-invasive bladder cancer (NMIBC) with intravesical Bacillus Calmette-Guérin immunotherapy (BCG) after transurethral resection of the bladder tumor (TURBT) remains unknown. Therefore, the current study performed a systematic review and meta-analysis to examine the relationship between preoperative NLR and the prognosis of patients with NMIBC with intravesical BCG immunotherapy. METHODS: For this systematic review and meta-analysis, articles were retrieved from PubMed, Cochrane Library, Web of Science, and Embase databases from their inception to 14 May 2024. The role of NLR in predicting recurrence and progression in NMIBC was determined using pooled hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Seven articles were included in this meta-analysis, involving 4,187 patients. An elevated NLR was significantly associated with recurrence (HR = 2.67, 95% CI = 1.34-5.32, P < 0.001) and progression (HR = 1.72, 95% CI = 1.13-2.60, P = 0.004) in patients with NMIBC with intravesical BCG immunotherapy. CONCLUSION: This meta-analysis demonstrated that elevated preoperative NLR levels were significantly associated with recurrence and disease progression in patients with NMIBC who underwent intravesical BCG immunotherapy after TURBT. SYSTEMATIC REVIEW REGISTRATION: https://inplasy.com/inplasy-2024-7-0058/, identifier 202470058.	bladder
Association of viral infection with bladder cancer: A systematic review and meta-analysis.	BACKGROUND: Bladder cancer (BC) is the tenth most common cancer with the highest mortality rate. Since the etiological role of viral infection in the development of BC is less known, the aim of the present study was to examine the pooled prevalence and possible relationship between viral infection and BC. METHODS: A systematic search of major online databases was conducted to investigate relevant studies. We estimated the pooled odds ratio (OR), 95 % confidence interval (CI), and heterogeneity for all studies by using meta-analysis and forest plots. All data were analyzed using Stata Software v.14.1. RESULTS: We analyzed 87 articles (97 datasets), which included 59 case-control and 38 cross-sectional designs. The pooled prevalence of viral infection among BC patients was 17.59 % (95 % CI: 13.09-22.55 %; I(2) = 96.34 %). Our subgroup analysis indicated that the pooled prevalence of human herpesvirus (HHV), papillomavirus (HPV), polyomavirus, and adenovirus was 33.67 %, 15.18 %, 7.46 %, and 30.14 %, respectively. We detected a significant relationship between viral infection and BC [summary OR 2.34 (95 % CI 1.56-3.51; I(2) = 58.0 %)]. CONCLUSIONS: This possible association was exhibited for Epstein-Barr virus (EBV) and HPV. Our finding indicated that HPV and EBV infections with significant associations with BC can be considered as possible risk factors for BC. Although the specific molecular mechanism of the role of viruses in the development of BC has not been identified, persistent viral infection, oncogenic protein expression, apoptosis inhibition, cell cycle promotion, and disruption of signaling pathways in bladder tissue are possible pathways for the role of viruses in the development of BC.	bladder
DNA Damage Response Alterations Predict for Neoadjuvant Chemotherapy Sensitivity in Muscle-Invasive Bladder Cancer: A Correlative Analysis of the SWOG S1314 Trial.	PURPOSE: Alterations in DNA damage response (DDR) genes, including ERCC2, have been correlated with response to neoadjuvant cisplatin-based chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC). The SWOG 1314 (S1314) trial enrolled patients with MIBC who received one of two NAC regimens followed by radical cystectomy. We examined the prevalence of DDR alterations in NAC responders versus nonresponders and correlated DDR alteration status with response. METHODS: Pretreatment tumor specimens from 179 evaluable patients underwent next-generation sequencing (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets assay). Associations were determined between any or only deleterious alterations within nine predefined DDR genes, or any alterations in ERCC2, and progression-free survival (PFS) and overall survival using Cox regression, and, in a subset of evaluable patients, pathologic response (complete response, pT0, or downstaging to <pT2) using logistic regression, adjusting for clinical stage and performance status. RESULTS: Deleterious DDR alterations were detected in 41 (23%) of 179 patients. Of the 151 patients evaluable for pathologic response, patients with deleterious DDR alterations (n = 39) demonstrated a higher pathologic response rate than those without (odds ratio [OR], 3.24 [95% CI, 1.51 to 6.94]; P = .003). In 24 ERCC2-mutant patients, the OR for pT0 was 3.33 (95% CI, 1.35 to 8.22; P = .009) and for <pT2 was 2.33 (95% CI, 0.92 to 5.89; P = .073). The association between deleterious DDR alterations and PFS provided an estimate of hazard ratio, 0.54 (95% CI, 0.29 to 1.01; P = .053). CONCLUSION: Deleterious DDR alterations were associated with pathologic response following NAC in S1314. Functional validation of ERCC2 and other DDR alterations is underway to help refine such alterations as biomarkers of NAC in patients with bladder cancer.	bladder